Dal germinale al somatico nella identificazione di tumori ereditari

Transcription

1 Modena novembre 2010 Dal germinale al somatico nella identificazione di tumori ereditari Laura Ottini

2 Tendencies to develop cancer can be inherited Fletcher & Houlston, 2010

3 Cancer is a genetic disease Only a minority of cancer is familial Cancer-susceptibility gene passed through germline DNA transmission (gametes) Non-familiar cancer is referred to as sporadic Mutations and other genetic alterations are acquired during an individual s lifetime in cells of the body (somatic cells) Genetic changes of cancer cells, both inherited and somatic, contribute to the malignant phenotype Most genetic changes in cancer alter the normal control mechanisms of normal cell physiology

4 The Hallmarks of Cancer Hanahan and Weinberg, 2000 Negrini et al., 2010

5 Genomic Instability an hallmark of cancer: Hereditary vs Sporadic cancer mutator model oncogene-induced DNA replication stress model Negrini et al., 2010

6 Genomic Instability: MSI - CIN Hereditary cancer syndromes involve DNA repair enzymes HNPPC: MMR MYH-associated polyposis: BER Breast and ovarian cancer, leukemia and lymphomas: DSBs Skin cancer: NER

7 Colorectal cancer 2-5% Breast Cancer 5-10% 65-75% 20-30% Hereditary Familial Sporadic 65-75% 20-25% Hereditary Familial Sporadic

8 1% 70% 10% 20% Hereditary Familial Sporadic Male Breast Cancer Female Breast Cancer Breast Cancer 99%

9 Microsatellite Instability (MSI) MSI-positive colorectal tumors: proximal colon lymphocytic infiltrate poorly differentiated, mucinous or signet ring appearance better prognosis different response to chemotherapeutics Boland & Goel. Gastroenterology, 2010

10 MSI in colon cancer

11 MSI in colon cancer

12 MSI in gastric cancer

13 Expression profile in gastric cancer with MSI Immune and apoptotic gene networks efficiently discriminate MSI-positive and MSI-negative (MSS) GCs. The DNA repair gene expression profile of MSI GCs is of relevance for therapy response.

14 BRCA1/2-associated Breast Cancer BRCA1 cancers are characterized by morphological, immunohistochemical and molecular features that can help triage patients who should be subjected to BRCA1 testing. Novel therapeutic strategies for the management of BRCA1 and BRCA2 cancer are emerging (cross-linking agents and PARP1 inhibitors). Da Silva & Lakhani, 2010, Flanagan et al., 2010

15 Male Breast Cancer 1% 70% 10% 20% Hereditary Familial Sporadic Male Breast Cancer Female Breast Cancer Breast Cancer 99%

16 Male Breast Cancer Rare Disease Estrogen Progesteron Unaffected by the strong confounding effects of reproductive-history related variables Male Breast Cancer Female Breast Cancer

17 Male vs Female Breast Cancer (Ottini et al. Crit Rev Oncol Hematol 2010)

18 Male vs Female Breast Cancer Gene Copy Number Variation: different biological processes are involved in male and female breast cancer (Tommasi S et al., 2010) Gene expression profiles: almost 1000 genes were found differentially expressed between male and female breast tumors (Callari M et al., 2010) microrna expression: MBC displays several differentially expressed micrornas, not all of them shared with FBC (Lehmann U et al., 2010)

19 Molecular epidemiology of Male Breast Cancer: interactions between genetic and environmental factors Characterize the genetic and phenotypic features of MBC from a large and epidemiologically well-characterized population-based series Identify geneenvironment interactions

20 Molecular epidemiology of Male Breast Cancer

21 Genetic and Epigenetic Signatures in Male Breast Cancer: a Multicenter Study in Italy Mi Pd Aviano Ge Mo Fi Fi Rm Rm Na Ba 366 MBC cases 600 Controls Pa